Rosuvastatin, 7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-(methyl-methylsulfonyl-amino)-pyrimidin-5-yl]-3,5-dihydroxy-hept-6-enoic acid, and its use in the inhibition of the biosynthesis of cholesterol was first disclosed in EP 0521471. Rosuvastatin is a potent inhibitor of HMG-CoA enzyme.
Trans-6-[2-(3- or 4-carboxamido-substituted pyrrol-1-yl)alkyl]-4-hydroxypyran-2-one compounds are lactones which were first disclosed in U.S. Pat. No. 4,681,893. This document also disclosed their corresponding ring opened acid equivalents i.e. atorvastatin and its analogues which have activity as HMG-CoA inhibitors. The lactone compounds, however, apparently do not have intrinsic activity of their own. The corresponding ring-opened acid equivalents are useful as cholesterol biosynthesis inhibitors because of their HMG-CoA activity. Also disclosed in U.S. Pat. No. 4,681,893 are various methods of manufacture for such compounds.
Atorvastatin, which is the R form of the ring-opened acid of trans-5-(4-fluorophenyl)-2-(1-methylethyl)-N,4-diphenyl-1-[2-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1H-pyrrole-3-carboxamide, and its use in the inhibition of the biosynthesis of cholesterol was first disclosed in EP 0409281. Atorvastatin both in racemic form, and in the form of its [R—(R*,R*)] isomer is a potent inhibitor of HMG-CoA enzyme.
Clin Invest Med, Volume 24, No 5, p258-72, 2001 (Baker and Tamopolsky) discloses that whilst statins having an open, hydroxy acid conformation are active, the lactone, closed-ring analogue is inactive. Hepatic hydrolysis at alkaline pH decyclises and hence activates the lactone prodrugs lovastatin and simvastatin in vivo by formation of the active ring opened species. However, one problem with such compounds is that extensive first path metabolism leads to rapid clearance of the resulting ring opened statin.
Similarly, Trends in Pharmacological Sciences, Volume 19, Issue 1, 1 Jan. 1998, Pages 26-37 discloses that the inactive lactones must be metabolised to their corresponding open hydroxy acid forms in order to inhibit HMG-CoA reductase.
The lactone form, and also the ring opened active form, may also suffer problems in terms of stability over an extended period of time. This represents a significant problem during manufacture of an active principal or during extended storage of the same in a pharmacy. For example, loss of the hydroxy group in a dehydration reaction may occur. The resulting decomposition product may have a double bond that is conjugated with the lactone carbonyl group and this will tend to favour the potential decomposition product. Equally, in the ring opened form, one of the possible decomposition products could also have a conjugated double bond with the acid carbonyl group.